The control and eventual elimination of malaria in Africa is seriously challenged by drug resistance, in particular resistance to new artemisinin-based combination therapy (ACT) regimens. Worrisome signs suggest that high level resistance to components of ACT is on the way to Africa, a scary prospect, since the bulk of serious falciparum malaria occurs on this continent. Improved characterization of the extent of resistance and mechanisms of resistance is of critical importance. We hypothesize that antimalarial drug resistance is increasing in Uganda, that the rise of resistance will be dampened and obscured by parasite fitness costs, but that continued drug pressure will allow emergence of resistant parasites that maintain adequate fitness to spread readily. Preemptive analysis of parasites will be critical to characterizing resistance mechanisms before the problem is widespread. To test our hypotheses we will monitor the drug sensitivities of malaria parasites isolated from Ugandan patients under varied levels of drug pressure; characterize the genetic profiles of these parasites; assess the fitness, virulence, and transmissibility costs of resistanc in both clinical and laboratory settings; and characterize high level resistance selected clinicall or in the laboratory. We believe that focused evaluations of fresh Ugandan isolates will best equip us to characterize the emergence of high level resistance in Africa, where the malaria problem is greatest, and where timely characterization of resistance mechanisms can be most valuable. Our studies will benefit from access to a wealth of clinical trials in Uganda, studying the treatment and chemoprevention of malaria, and providing fresh isolates for genetic and parasitological evaluation. They will also benefit from our established laboratories for the study of malaria parasites in Kampala and Tororo. We believe that, to well characterize resistance, it is essential to study fresh isolates that have not yet lost key determinants in culture. Our specifc aims will be: (1) to assess impacts of selective pressures for resistance of malaria parasites to ACTs used for the treatment and chemoprevention of malaria, (2) to characterize phenotypes associated with diminished drug sensitivity, and (3) to identify mediators of high level drug resistance. Our overall goal is to better characterize antimalarial drug resistance and resistance determinants before the problem becomes widespread in Africa, so that monitoring of these determinants can guide efforts to circumvent the spread of resistance.